A major obstacle to the widespread application of implantable glucose sensors is that they progressively lose function after a relatively short period of time in vivo. This loss of function is in part a consequence of inflammation and fibrosis resulting from the tissue trauma caused by the sensor implantation and by reactions within the tissue. For an implantable glucose sensor, mere tissue toleration of the device is not sufficient; the sensor must also remain functional. It must be emphasize that although it is known that tissue reactions plays an important role in loss of sensor's function, the specific contribution of each tissue reactions (i.e. inflammation, fibrosis and loss of vasculature) has not yet been determined nor quantified. Furthermore, little work has been done so far on controlling these reactions to implanted biosensors. Based on the preceding information, we have developed the following hypotheses. Grant Hypotheses: We hypothesize that inflammation, fibrosis and loss of vasculature affect both the transport properties and the local concentration of glucose around the implanted sensor. As a result, implanted glucose sensors progressively lose function and become unreliable after implantation. We further hypothesize that our experiments and mathematical models will show that all three-tissue reactions play a significant role in the loss of sensor function. However, we also hypothesize that use of an anti-inflammatory drug delivery system, with an anti-fibrotic decorated surface hydrogel, and VEGF gene transfer can enhance the function and lifespan of the implanted sensors by decreasing inflammation and fibrosis, as well as by enhancing neovascularization. To test these hypotheses, we propose to use the current electrochemical Nation-based glucose sensor developed in our laboratory and all in vivo experiments will be conducted in the rat model. Therefore, the goals of this proposal will be: 1) to determine the specific contributions of inflammation, fibrosis and blood vessel density on the sensor's loss of function, using in vitro and in vivo studies as well as mathematical models, and 2) to control these reactions using a combination of approaches (decorated hydrogels, drug delivery and gene transfer) to enhance the glucose sensor's function and lifetime in vivo. Our overall goal for this proposal is to have a glucose sensor that can be implanted and provide reliable and continuous monitoring for at least 4 weeks.